CN101563466A - Modified release amoxicillin products - Google Patents

Modified release amoxicillin products Download PDF

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Publication number
CN101563466A
CN101563466A CNA2006800522414A CN200680052241A CN101563466A CN 101563466 A CN101563466 A CN 101563466A CN A2006800522414 A CNA2006800522414 A CN A2006800522414A CN 200680052241 A CN200680052241 A CN 200680052241A CN 101563466 A CN101563466 A CN 101563466A
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CN
China
Prior art keywords
product
auc
component
administration
amoxycilline trihydrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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CNA2006800522414A
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Chinese (zh)
Inventor
D·特里西
A·R·波茨
H·H·弗兰纳
B·A·伯恩塞德
S·托尔-桑德
S·P·克劳森
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MiddleBrook Pharmaceuticals Inc
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Advancis Pharmaceutical Corp
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Publication date
Priority to US11/633,315 priority Critical
Priority to US11/633,315 priority patent/US8778924B2/en
Priority to US11/634,633 priority
Application filed by Advancis Pharmaceutical Corp filed Critical Advancis Pharmaceutical Corp
Publication of CN101563466A publication Critical patent/CN101563466A/en
Pending legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents

Abstract

Disclosed are amoxicillin products comprising at least one modified release component(s), wherein the at least one modified release component(s) comprises at least amoxicillin and a pharmaceutically acceptable carrier. In some embodiments, when administered to a patient or subject in the fed state the amoxicillin products exhibit a pharmacokinetic profile for amoxicillin in the plasma characterized as follows: (1) the ratio of the portion of the AUC as measured from 2 hours post-administration to 5 hours post-administration to the portion of the AUC as measured from administration to 2 hours post- administration is at least 2.0: 1 : and (2) the ratio of the portion of the AUC as measured from 5 hours post-administration to 12 hours post-administration to the portion of the AUC as measured from administration to 2 hours post-administration is at least 1.1:1. In additional embodiments the amoxicillin products exhibit a mean in-vitro dissolution profile within a defined range characterized as follows: 1) the percent dissolved at 0.25 hours is between 25 and 55 percent; 2) the percent dissolved at 0.5 hours is between 30 and 60 percent; 3) the percent dissolved at 1 hour is between 50 and 85 percent; 4) the percent dissolved at 1.5 hours is between 70 and 95 percent; and 5) the percent dissolved at 2 hours is at least 85 percent. In preferred embodiments the amoxicillin products exhibit both of these characteristics.

Description

The amoxicillin products of the release of modifying
The present invention relates to amoxicillin products and using method thereof.
Twice of every day (b.i.d.), wherein per 12 hours administration compositions once; Every day three times (ti.d.), wherein per 8 hours administration compositions once; Four times a day (q.i.d.), wherein per 6 hours administration compositions are once; Perhaps described dosage regimen even it is contemplated that to surpass four administration compositions every day.
Can also in the preparation of the release of modifying, utilize the amoxycilline Trihydrate bp, for example, with the preparation of trade mark AUGMENTIN XR sale.
The present invention relates to amoxicillin products and application thereof, wherein all or part of amoxycilline Trihydrate bp exists with the release component of modifying.
In one embodiment, in one way amoxicillin products is prepared, made (x) amoxicillin products have feasible (i) from the average A UC part of 2 hours amoxicillin products during 5 hours to the administration after the administration and the average A UC that (ii) is at least 2.0: 1 from the ratio that is administered to the average A UC part of the amoxicillin products during 2 hours after the administration; (y) (iii) from the average A UC part of 5 hours amoxicillin products during 12 hours to the administration after the administration with (ii) be at least 1.1: 1 from the ratio that is administered to the average A UC part of the amoxicillin products during 2 hours after the administration.
The AUC of fixed time limit (area under a curve) is called as " the part A UC " of this section period.
The AUC that in specification sheets and claim, uses (0-2)Be meant basically the amoxycilline Trihydrate bp AUC part of measuring according to the method for embodiment 1 after 2 hours from the time 0 to the administration amoxicillin products.AUC (2-5)Be meant basically 2 hours to 5 hours the amoxycilline Trihydrate bp AUC part of measuring according to the method for embodiment 1 after the administration amoxicillin products.
AUC (5-12)Be meant basically 5 hours to 12 hours the amoxycilline Trihydrate bp AUC part of measuring according to the method for embodiment 1 after the administration amoxicillin products.
In one embodiment, amoxicillin products has at least 2.2: 1 AUC (2-5)With AUC (0-2)Ratio, and in another embodiment, be at least 2.4: 1.
In another embodiment, AUC (5-12)With AUC (0-2)Ratio be at least 1.2: 1 or at least 1.3: 1.
Usually, AUC (2-5)With AUC (0-2)Ratio be no more than 10: 1, perhaps be no more than 8: 1 in some cases or in other situation, be no more than 6: 1.
Usually, AUC (5-12)With AUC (0-2)Ratio be no more than 10: 1, perhaps be no more than 8: 1 in some cases or in other situation, be no more than 6: 1.
Purpose for specification sheets and claims, can be basically according to embodiment 1, by the higher fatty acid or lower fat feed state scheme of using embodiment 1 amoxicillin products is tested, if and test it according to arbitrary feed state scheme basically and fall in the described scope, think that so described amoxicillin products falls in the specified range of part A UC ratio.
Term " amoxycilline Trihydrate bp " should broadly be understood as used herein, not only comprising this activeconstituents, but also comprises all polymorphic forms, salt and/or its hydrate.
Be known in the art, the AUC (area under a curve) of amoxycilline Trihydrate bp in human plasma is administered to amoxicillin products after the mankind, the pharmacokinetics profile of amoxicillin products in human plasma, wherein AUC is that the concentration human plasma makes that as the area under a curve that the functional arrangement of time after the administration obtains Y-axis is that concentration and the X-axis of amoxycilline Trihydrate bp in human plasma is time after the administration after the administration amoxicillin products from the amoxycilline Trihydrate bp.
Aforementioned proportion is determined according to the method described in the embodiment 1 basically, wherein determine the pharmacokinetics profile according to embodiment 1 by the amoxicillin products of administration single dose under the state on the feed basically, obtain the human plasma sample and analyze according to embodiment 1 basically, and determine the AUC ratio according to embodiment 1 basically.
Embodiment 1 is provided as and determines whether amoxicillin products has the analysis tool of part A UC ratio mentioned above.The described analysis tool of this embodiment does not only limit the invention on the feed the human amoxicillin products of administration under the state; And do not limit the invention to handle the patient according to the scheme of embodiment 1.
The result, as in specification sheets and claim, using, part A UC ratio is basically according to embodiment 1 ratio determined down of state on the feed, even amoxicillin products is used or administration in the mode that is different from embodiment 1, even and in any adjustable layout, determine AUC and/or part A UC in the mode that is different from embodiment 1 at amoxicillin products.
In another embodiment, the present invention relates to comprise the amoxicillin products of the release component of at least a modification, it has average dissolution in vitro profile when testing according to the method for embodiment 8, wherein when following preset time, total dissolving per-cent of amoxycilline Trihydrate bp is at least the minimum dissolving per-cent of regulation and is no more than the maximum dissolving per-cent of regulation in the product, and is as follows:
Time (hour) Minimum (%) Maximum (%)
0.25 25 55
0.5 30 60
1 50 85
1.5 70 95
2 85 -
In one embodiment, amoxicillin products has and falls into average dissolution in vitro profile in the following dissolving percentage range in preset time:
Time (hour) Minimum (%) Maximum (%)
0.25 30 50
0.5 35 55
1 55 80
1.5 75 90
2 90 -
In another embodiment, amoxicillin products has and falls into average dissolution in vitro profile in the following dissolving percentage range in preset time:
Time (hour) Minimum (%) Maximum (%)
0.25 35 45
0.5 35 45
1 65 75
1.5 75 85
2 90 -
Average dissolution in vitro profile is to determine according to the dissolving method of embodiment 8.The average result that utilizes the dissolving method of embodiment 8 to produce will show the %RSD (relative standard deviation) less than 10% usually.
Thus, when mentioning the average dissolution in vitro profile of amoxicillin products in specification sheets and the claim, use the dissolving method of embodiment 8 to determine whether amoxicillin products has at the minimum of regulation and the average dissolution in vitro profile in the maximum dissolving per-cent when preset time.
The interior dissolving of the body profile that should be appreciated that amoxicillin products can fall into or can not fall in the average dissolution in vitro profile scope mentioned above.
Though be not intended thus specification sheets and claim to be limited, amoxicillin products is prepared so that it has average dissolution in vitro profile described herein, thus the T of prolongation amoxicillin products MaxThereby minimum inhibitory concentration (MIC) time with prolonging in blood plasma, keep acceptable area under a curve (AUC) simultaneously.
In embodiments of the invention, provide the amoxicillin products of the release component that comprises at least a modification, when with the fasting state administration, described product have with the feed state under identical degree of absorption during the described product of administration.
As used herein in 80%~125% the scope that " identical degree of absorption " is meant that being absorbed under fasting state absorb under the feed state, has 90% fiducial interval, as FDAGuidance for Industry-Food-Effect Bioavailability and Fed BioequivalenceStudies, described in the December 2002.
According to described principle, determine that the scheme of degree of absorption under " fasting state " is meant at least after overnight fast 10 hours, should give medicament production and 240mL (8 fluid ounce) water to the experimenter.Behind dosed administration, at least 4 hours, do not allow any feed.In one hour before and after drug administration, can provide beyond the water as required.In each time of research, the experimenter should accept periodic standard diet simultaneously.According to described principle, determine " feed state " down the scheme of degree of absorption be meant that after overnight fast 10 hours the experimenter should begin to accept recommended dietary 30 minutes the time before the administration medicine product at least.The research experimenter should or still less eat these meals in the time at 30 minutes; Yet medicament production should begin the administration afterwards in 30 minutes of taking food.Should be with 240mL (8 fluid ounce) water administration medicine product.Behind dosed administration, at least 4 hours, do not allow any feed.In one hour before and after drug administration, can provide beyond the water as required.In each time of research, the experimenter should accept periodic standard diet simultaneously.
" recommended dietary " is meant: higher fatty acid (meals total enthalpy about 50%) and high calorie (about 800~1000 calories) meals are recommended the test meals studied as food effect BA (bioavailability) and feed BE (bioequivalence).These test meals should produce about 150,250 and the 500-600 calorie respectively by protein, carbohydrate and fat.For fasting and feed state, the method for embodiment 1 is abideed by described guide.
The degree that absorbs is determined by area under a curve (AUC) usually.The AUC that general report is two types generally is referred to as AUC 0-t, wherein AUC calculates in the time range of the time t that extracts last plasma sample from zero, and AUC 0-∞Usually be represented as AUC , wherein calculate AUC With it is added and arrives AUC 0-tOn.AUC T-∞Be extrapolated to infinite point and obtain from time t, it is based on the activity component concentration of being determined by the concentration extrapolation of last measurement according to the elimination speed of determining from single number of subjects and reaches 0 time point.
The amoxicillin products that is formulated into the release component that comprises at least a modification with part A UC ratio mentioned above and/or dissolution in vitro profile can be produced with multiple amoxycilline Trihydrate bp form and dosage, and can be according to multiple different scheme administration; Twice of every day, every day three times for example once a day.
In one embodiment, product comprises immediate-release component and postpones to discharge component.
In another embodiment, product comprises immediate-release component and two kinds or more kinds of delay release component.
In another embodiment, product comprise a kind of, two or three or more kinds of delay discharge component and do not contain immediate-release component.
In another embodiment, product comprises a kind of, two kinds or more kinds of time-delay and discharges (slowly-releasing) component and do not contain immediate-release component.
In another embodiment, product comprises immediate-release component and a kind of, two kinds or more kinds of time-delay release component.
In another embodiment, product comprises that immediate-release component and one or more postpone to discharge the combination of component and one or more time-delay release components.
As using herein and well known in the art, immediate-release component is after the administration product, and the beginning of the release of activeconstituents and/or rate of release are not delayed basically and/or slow down and/or the component of slowly-releasing.With well known in the art, the release component of modification is not an immediate-release component as used herein.The limiting examples of the release component of described modification comprises: do not discharged component as wherein discharging in for some time after postponing by the delay of a kind of component that continues, and as being released in for some time of activeconstituents wherein, and/or above-mentioned combination by the slowly-releasing of a kind of component that continues (perhaps time-delay discharges) component.Discharging, postpone release and slowly-releasing (time-delay) release component immediately is component well known in the art and term, and it is formulated in those skilled in the art's the limit of power.Disclosure and U.S. Patent Application Serial 10/894,787 based on this paper; 10/894,786; 10/894,994; 10/917,059; 10/922,412; With 10/940,265 disclosure; And United States Patent (USP) 6,544,555; 6,623,757; With 6,669, the further instruction of 948 disclosure, the application of the multiple combination of said components will be conspicuous for those of ordinary skills; Its full content is incorporated herein by reference.According to embodiment of the present invention, no matter what the various ingredients of using in the amoxicillin products of the release component that contains at least a modification is, described component is prepared, thereby made amoxicillin products have part A UC mentioned above.
According to a kind of embodiment of the present invention, there are at least two kinds of components (wherein at least a release component) for modifying.A kind of at least two kinds of components is immediate-release component, thus after the composition of administration amoxycilline Trihydrate bp wherein the release of amoxycilline Trihydrate bp start and not to be delayed basically, perhaps for postpone discharging component, thus after the composition of administration amoxycilline Trihydrate bp wherein the release of amoxycilline Trihydrate bp be delayed basically.(each postpones to discharge component can be that pH delay responsive or non-pH sensitivity discharges component in order to postpone discharging component at least two kinds of components second kind, this depends on the type of amoxycilline Trihydrate bp composition), be delayed from the amoxycilline Trihydrate bp that wherein discharges thus, till the amoxycilline Trihydrate bp in the release immediately or the first delay release component begins to discharge.More particularly, the amoxycilline Trihydrate bp that discharges in first kind from least two kinds of components reaches C in blood plasma MaxAfterwards, the amoxycilline Trihydrate bp that discharges from second kind of at least two kinds of components reaches C Max(maximal plasma concentration).
According to a kind of embodiment of the present invention, there are at least three kinds of components (wherein at least a release component) for modifying.A kind of at least three kinds of components is immediate-release component, and thus after the composition of administration amoxycilline Trihydrate bp, wherein the beginning that discharges of amoxycilline Trihydrate bp is not delayed basically.(each postpones to discharge component can be that pH delay responsive or non-pH sensitivity discharges component in order to postpone discharging component at least three kinds of components second kind and the third, this depends on the type of amoxycilline Trihydrate bp composition), be delayed from the amoxycilline Trihydrate bp that wherein discharges thus, till the amoxycilline Trihydrate bp in immediate-release component begins to discharge.More particularly, the amoxycilline Trihydrate bp that discharges in first kind from least three kinds of components reaches C in blood plasma MaxAfterwards, the amoxycilline Trihydrate bp that discharges from second kind of at least three kinds of components reaches C Max(maximal plasma concentration), and reach C in the amoxycilline Trihydrate bp that from second kind of component, discharges MaxAfterwards, the amoxycilline Trihydrate bp that discharges from the third component reaches C in blood plasma Max
In one embodiment, after first kind of component at least one hour, second kind at least three kinds of components begins to discharge the amoxycilline Trihydrate bp of wherein containing, simultaneously being released in when amoxycilline Trihydrate bp in first kind of component at least three kinds of components is no more than six hours after beginning to discharge and beginning to take place wherein.
As indicated above, some amoxycilline Trihydrate bp composition embodiments can contain two kinds, three kinds, four kinds or more kinds of different component (condition be at least a be the release component of modifying).
In a kind of three component embodiments, the amoxycilline Trihydrate bp that discharges from the third component reaches C being later than the amoxycilline Trihydrate bp that discharges from first and second kinds of components MaxTime reach C MaxIn preferred embodiments, the release that is released in the amoxycilline Trihydrate bp in first kind of component and the second kind of component of amoxycilline Trihydrate bp starts after beginning in the third component.In one embodiment, the C of the amoxycilline Trihydrate bp that from the third component, discharges MaxIn 8 hours, reach.
In another kind of three component embodiments, the release of amoxycilline Trihydrate bp can begin simultaneously with the release of amoxycilline Trihydrate bp in first component in second component.
In another kind of three component embodiments, the release of amoxycilline Trihydrate bp can begin simultaneously with the release of amoxycilline Trihydrate bp in second component in the 3rd component.
In another embodiment, the amoxycilline Trihydrate bp composition can contain four kinds of components (wherein at least a is the component of the release of modification), four kinds of components have different release profiles separately, and each comfortable different time of the release of amoxycilline Trihydrate bp reaches C in four kinds of different components thus Max
In a kind of embodiment preferred, amoxicillin products contain at least two kinds or at least three kinds or at least four kinds different have the different components that discharge profiles separately, the C that from amoxicillin products, discharges of amoxycilline Trihydrate bp wherein MaxIn less than 12 hours, reach all, and be more typically in 11 hours and reach.
In one embodiment, amoxicillin products is a composition once a day, after the administration amoxicillin products, does not need further administration composition the same day thus; That is, this dosage regimen is that only the administration product is once in the time at twenty four hours.Thus, according to this embodiment, the single-dose amoxicillin products, wherein the amoxycilline Trihydrate bp is so that overall amoxycilline Trihydrate bp discharges the mode that realizes with different release profiles to be discharged, and makes the overall C of amoxycilline Trihydrate bp composition MaxIn less than 12 hours, reach.Term " single-dose " is meant that whole amoxycilline Trihydrate bps in twenty four hours administration in the time are by the while administration, it can be single dose unit (tablet, capsule or smalls/pouch) or its two kinds or multiple-unit more, and condition is that they are basically by the while administration.
In one embodiment, described product once a day discharges component by immediate-release component and two kinds of delays and forms, wherein the first delay release component begins to discharge the amoxycilline Trihydrate bp after discharging from immediate-release component in the amoxycilline Trihydrate bp, and the second delay release component discharges the amoxycilline Trihydrate bp after the amoxycilline Trihydrate bp discharges since the first delay release component.
In amoxicillin products once a day, described product has part A UC ratio same as described above and/or dissolution in vitro profile.
In one embodiment, amoxicillin products is twice product every day, thus after initial administration amoxicillin products, at further administration amoxicillin products of another time on the same day; That is, this dosage regimen is at twenty four hours twice of administration composition only in the time.
In one embodiment, every day, twice amoxicillin products comprised two kinds or more kinds of component, and a kind of in described two kinds of components is the release component of modifying for the another kind in immediate-release component and the two kinds of components.
In another embodiment, every day, twice amoxicillin products contained the release component of a kind of immediate-release component and two kinds or more kinds of modifications, and specific embodiments comprises the release component of two kinds of modifications.
In every day twice amoxicillin products, described product has part A UC ratio same as described above and/or dissolution in vitro profile.
Thus, according to a kind of embodiment, every day twice administration amoxicillin products, wherein the amoxycilline Trihydrate bp is so that the mode that the release of overall amoxycilline Trihydrate bp realizes with different release profiles discharges the product overall C separately that makes twice administration MaxEach comfortable administration reached in 12 hours.The dosage of each administration can be single amoxicillin products or multiple amoxicillin products in twice administration.
In one embodiment, the amoxicillin products mentioned above with above-mentioned part A UC ratio and/or dissolution in vitro profile has at least 75% (AUC of the degree of absorption that the amoxicillin products that the amoxycilline Trihydrate bp discharges immediately only is provided 0-∞), and in preferred embodiments, at least 80% (AUC of degree of absorption 0-∞).Usually, the degree of absorption (AUC of amoxicillin products of the present invention 0-∞) be no more than the degree of absorption (AUC that the amoxicillin products that the amoxycilline Trihydrate bp discharges immediately only is provided 0-∞).In comparative product determining in the degree of absorption, on the feed state or in fasting state AUC 0-∞Be to determine, and every kind of product have the amoxycilline Trihydrate bp of same amount according to the FDA guidance for industry that above relates to.
When amoxicillin products was administered orally to the mankind, described product was taken under state or the fasting state on the feed, is preferably taken under the state on the feed.
As known in the art, described product on the feed or be administered orally to the mankind under the fasting state and have and be different from the implication that the FDA that is used to test degree of absorption requires.Just product is administered to humanly using with regard to the product, the feed state means together with food (before the pickuping food immediately, simultaneously or after pickuping food just).Fasting or non-feed state mean not with ingestion of food.
Should be appreciated that this term is meant that this component is designed to or is intended to be used to produce the described release that began afterwards when disclosing a kind of component in this article and begin to discharge after another component.Yet, be known in the art, although have described design and intention, some antibiotic " seepages " also may take place.Described " seepage " is not " release " used herein.
Amoxicillin products of the present invention, as noted before, can be used for by multiple route of administration administration by preparation.For example, the amoxycilline Trihydrate bp composition can be prepared in the mode that is applicable to following administration: topical; Administration in eyes or ear; Rectum or vagina administration; As nasal formulations; Inhalation; Drug administration by injection; Perhaps oral administration.In preferred embodiments, so that its mode that is suitable for oral administration is prepared the amoxycilline Trihydrate bp composition.
For example, the amoxicillin products that is used for topical in preparation, such as carrying out topical on the skin, can the various component preparations that contain the amoxycilline Trihydrate bp be used for topical by described component being included in oil-in-water emulsion or the water-in-oil emulsion by being applied to.In described preparation, immediate-release component can be in external phase, and postpone to discharge component can be in discontinuous phase.Can also produce described preparation in one way to be used to send three kinds of components mentioned above.For example, can provide water-in-oil bag oil emulsion, oily for containing the external phase of immediate-release component, the water that is dispersed in the oil contains the first delay release component, and the oil that is dispersed in the water contains the 3rd delay release component.
The amoxicillin products of patch form also is provided within the scope of the present invention, and it comprises the different amoxycilline Trihydrate bp components that discharge profile that have as indicated above.In addition, amoxicillin products can be used for eyes or ear or nose by preparation, for example as liquid emulsion.For example, can apply hydrophobic polymer to component, this component is in the oil phase of emulsion thus, and can apply hydrophilic polymer to component, and this component is in the aqueous phase of emulsion thus.
In addition, the amoxicillin products with release component (no matter whether uniting so that multiple different release profile to be provided with other component) of at least a modification can be formulated into and be used for rectum or vagina administration, as known in the art.It can take the form of emulsifiable paste, emulsion, suppository or other the solubilized component similar to those forms that are used for topical.The form that depends on product, amoxicillin products can contain the amoxycilline Trihydrate bp of the amount of the 200mg that has an appointment~about 2500mg.As non-limiting instance, amoxicillin products can contain 475mg or 775mg or 1250mg or 1550mg or 2325mg amoxycilline Trihydrate bp.
In preferred embodiments, prepare amoxicillin products in the mode that is applicable to oral administration.Thus, for example,, can be the unit pharmaceutical composition with pill or shaping particles then, for example in capsule or the Inlay-Tabs, for smalls or be suspended in the liquid of oral administration with every kind of component as pill or particle for oral administration.In a kind of non-limiting embodiments, tablet disintegration rapidly becomes tablet, and the various ingredients of product is released by absorption thus, further is transported in the intestines with the form of pill or granula.
Additionally, when preparation oral delivery system, the various set of dispense of composition can be made tablet, thereby various tablets are incapsulated the productive unit amoxicillin products.Thus, as its limiting examples, three component amoxicillin products can comprise and be conduct first component of the tablet form of release tablet immediately, and can comprise two kinds or more kinds of other tablet, the delay release or the slowly-releasing of amoxycilline Trihydrate bp are provided separately, as indicated above.
Amoxicillin products can be the form of smalls product; For example the product component of multiple particle form (for example being pill) is placed pouch, capsule or other form of the component that can be used for the particle form of administration simultaneously.
According to instruction herein, that thinks that preparation is used for different way of administration contains at least three kinds of amoxicillin products with different components that discharge profiles within those skilled in the art's limit of power.As known in the art, discharge about postponing, can be by number of mechanisms to controlling time of releasing, these mechanism for example are the selection of pH trigger point, coat-thickness, polymkeric substance, selection, osmotic pressure, physical expansion pressure and the above-mentioned combination of fluidizer.
In preparation during according to the amoxicillin products of one embodiment of this invention, immediate-release component accounts for about 45% of amoxycilline Trihydrate bp total dose in the product usually, first postpone to discharge component accounts for 30% of amoxycilline Trihydrate bp total dose in the product usually, and second postpones to discharge about 25% (all by weight) that component accounts for amoxycilline Trihydrate bp total dose in the product usually.This embodiment is also nonrestrictive, and when all other knowledge that should have with those of ordinary skills when content disclosed herein is considered, those of ordinary skills can recognize easily and be different from those component percentages of pointing out in this unrestricted embodiment, when forming amoxicillin products when mixing, these per-cents have part A UC ratio mentioned above and/or dissolution in vitro profile.
According to embodiment of the present invention, all contain the amoxycilline Trihydrate bp in every kind of component; Yet, can contain the activeconstituents of another kind of microbiotic or other type in every kind of component.
In embodiment mentioned above, amoxicillin products has part A UC ratio mentioned above and/or dissolution in vitro profile mentioned above.In a kind of embodiment preferred, amoxicillin products had both had and identical part A UC ratio mentioned above, also had and identical dissolution in vitro profile mentioned above.
Immediate-release component
The release portion immediately of this system can be to break rapidly after administration to discharge the mixture of ingredients of amoxycilline Trihydrate bp.It can be other component mixing in product or the form of separating tablet, pill or granula of compression.
In addition, it also is useful having other component in this system, with helping the dissolving of medicine or breaking of component after picked-up or administration.These compositions can be tensio-active agents, such as Sodium Lauryl Sulphate BP/USP, single sodium glycerinate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, only son's acid glyceride, a kind of non-ionic tenside, tensio-active agent such as poloxamer system, perhaps any other material, perhaps any combination of above-mentioned substance with some surface active property.
The delay of non-pH sensitivity discharges component
Component in the said composition still has the other polymkeric substance that is incorporated in the composition with releasing unit is identical immediately, perhaps is the dressing form on pill or the particulate.
The several method that postpones to discharge with non-pH dependent polymers influence all is that those skilled in the art are known.These comprise the capsule system of solubility or erodible barrier system, enzyme liberating barrier system, rupturable coat system and jam-pack.These systems at document (referring to " A Review of Pulsatile Drug Delivery ", Bussemer and Bodmeier, Winter2001 issue of American Pharmaceutical Review) carried out abundant description in, preparation and their preparation method are incorporated herein by reference.
The material that can be used to obtain to be applicable to the hang-over n. of this component of the present invention can be but be not limited to molecular weight and be higher than 4,000 daltonian polyoxyethylene glycol (PEG) (carbowax, Polyox), wax (such as Chinese wax or beeswax), paraffin, acrylic acid derivative (Eudragit), propylene glycol and ethyl cellulose.
These materials generally can be to exist in 0.5-40% (W/W) scope of this component.
PH sensitivity (enteron aisle) discharges component
Component in the said composition is identical with immediate-release component, but has the other polymkeric substance that is incorporated in the composition, and perhaps the dressing as pill or particulate discharges with delay.
Can be used for this purpose substance classes can for but be not limited to other phthalate of cellulose acetate phthalate, Eudragit L, Eudragit S, Eudragit FS and derivatived cellulose.
These materials can exist with the concentration of 4-30% (W/W).
The slowly-releasing component
Component in the said composition is identical with immediate-release component, but has an other polymkeric substance that is attached in the composition, perhaps for the dressing of tablet, pill or particulate so that slow releasing pharmaceutical to be provided.
Can be used for this purpose substance classes can for but be not limited to ethyl cellulose; Vltra tears; Hydroxypropylcellulose; Natvosol; Carboxymethyl cellulose; Methylcellulose gum; Nitrocotton; Eudragit R; Eudragit RS; With Eudragit RL; Carbopol; Perhaps molecular weight surpasses 8,000 daltonian polyoxyethylene glycol.
These materials can exist with the concentration of 4-40% (W/W).
When expectation postpones the beginning of release of slowly-releasing component, can use suitable dressing to postpone the beginning of slowly-releasing, the dressing of or non-pH sensitivity responsive such as pH.
The dressing of the non-pH sensitivity of slowly-releasing component
Can be used to obtain to be applicable to this component of the present invention release delay material can for but be not limited to molecular weight and be higher than 4,000 daltonian polyoxyethylene glycol (PEG) (carbowax, Polyox), wax (such as Chinese wax or beeswax), paraffin, acrylic acid derivative (Eudragit RS), cellulose ethanoate and ethyl cellulose.
These materials generally can exist in the scope of the 0.5-25% of this component (W/W).Preferred these materials are with time of lag and T in the body that expectation just is provided MaxAbundant amount exist.
The dressing of the pH sensitivity of slowly-releasing component
Can be used for this purpose substance classes can for but be not limited to other phthalate of cellulose acetate phthalate, Eudragit L, Eudragit S, Eudragit FS and derivatived cellulose.
These materials can exist with 4-30% (W/W) or higher concentration.Preferred these materials are with time of lag and T in the body that expectation just is provided MaxAbundant amount exist.
As indicated above, the unit that contains amoxycilline Trihydrate bp of the present invention composition can be for being included in separation pill or the particulate form in the capsule, perhaps is embedded in the tablet or is suspended in particulate form in the liquid suspension.
Amoxicillin products of the present invention is passable, for example carries out administration by following any route of administration: hypogloeeis, oral cavity, through skin, parenteral or the like, and preferred oral administration.Described product comprises the amoxycilline Trihydrate bp for the treatment of significant quantity, this amount will along with the disease that is intended to treat or infection and in one day this product be intended to the variation of the number of times sent and change.Product is administered to patient or experimenter (that is, the mankind or animal) with the significant quantity of treatment infectation of bacteria.
According to a kind of embodiment, when being administered to the mankind, amoxicillin products has the feasible whole amoxycilline Trihydrate bps that discharge from product maximal plasma concentration is being less than 12 hours, preferably is less than the overall release profile that reaches in 11 hours.
On the other hand, the invention provides the method for in the mankind, treating the multiple infection that causes by bacterial pathogen, comprise to patient or experimenter's administration amoxicillin products described herein.The limiting examples of the patient's indication that can be used for the treatment of as amoxicillin products that can mention is: pharyngitis, tonsillitis, sinusitis, bronchitis, pneumonia, otic infections (otitis media), uncomplicated skin and skin texture infect and uncomplicated urinary system infection.
Limiting examples as the infective bacterial venereal disease substance that can use the amoxicillin products antagonism, what can mention is the Gram-positive aerophil, such as streptococcus aureus, enterococcus faecalis, staphylococcus epidermidis, Staphylococcus saprophyticus, streptococcus pneumoniae, streptococcus pyogenes and multiple suis; Gram-negative aerobic bacteria is such as enterobacter class, intestinal bacteria, hemophilus influenzae, klebsiella, moraxelle catarrhalis, Aitken bacterium, gonococcus and Proteus mirabilis; Anerobe such as lopsided thalline class, comprises lopsided thalline, fusobacterium and Peptostreptococcus class.
In one embodiment, amoxicillin products is formulated into and is used for target tonsilla pharyngitis specifically, and the latter time is born in streptococcus pyogenes.
Those of ordinary skills are to be understood that, also be applicable to amoxycilline Trihydrate bp with the Clavulanate coupling for the described method and formulation of amoxicillin products, perhaps with the amoxycilline Trihydrate bp of other beta-lactamase inhibitor coupling, be specially adapted to treat the pathogenic agent of wherein producing β-Nei Xiananmei and come into the picture as primary infection or as the infection of co-infected.
In the treatment infectation of bacteria, amoxicillin products is prepared, reach for some time with the blood plasma amoxycilline Trihydrate bp concentration of effective treatment infectation of bacteria that the MIC that is higher than bacterial pathogen is provided every day.With amoxicillin products administration many days, thereby provide the blood plasma MIC concentration on the MIC of effective treatment infectation of bacteria to reach the total time (time every day on MIC be multiply by the treatment fate).
The present invention is described further with reference to following examples; Yet scope of the present invention is not limited by the examples.Unless otherwise mentioned, umber and per-cent are all by weight.
Embodiment 1
In the human experimenter, use the performance of single dose pharmacokinetic study with the release products of sign amoxycilline Trihydrate bp modification.
(a) feed state dosage regimen
Higher fatty acid dosage regimen: when the research of medicine-feeding test under higher fatty acid condition medicine, all experimenters will need fasting at least 10 hours, until before its periodic administration time 30 minutes, when they will be given higher fatty acid (account for greatly the whole thermal contents of meals 50%) and high calorie of (about 800~1000 calories) breakfast, breakfast will be by edible finishing fully in 30 fens clock times.Breakfast will be made up of 2 section buttered toast, 2 fried eggs, 2 bacons, 1 part of brown potato that chops up and 240mL full milk.The research medicine will be with 240mL water by administration.Except water was quantity-unlimiting during studying to dosage 1 hour in 1 hour before the dosage.All experimenters are continued fasting at least 4 hours after drug administration.
Lower fat dosage regimen: medicine-feeding test research medicine under stdn meals condition, all experimenters will need by fasting 10 hours at least, until 30 minutes before schedule dosed administration time, when they will take stdn breakfast (account for greatly the 25-30% of whole thermal contents of fatty diet and about altogether 470 calories), in 30 fens clock times by edible finishing fully.Breakfast will be made up of 2 section toasted breads and 1 soupspoon butter, 1 ounce of corn flakes cereal in the 120mL full milk, 150mL orange juice.The research medicine will be with 240mL water by administration.Except in that water was quantity-unlimiting during studying to dosage 1 hour in 1 hour before the dosage.All experimenters are continued fasting at least 4 hours after drug administration.
(b) fasting dosage regimen: medicine-feeding test research medicine under fasted conditions, all experimenters will need by fasting 10 hours at least before dosed administration.Except in that water all allowed to take during studying to dosage 1 hour in 1 hour before the dosage.All experimenters are continued fasting at least 4 hours after drug administration.
(c) drug administration scheme
Though under the condition, each experimenter will be in the morning at 0 o'clock on the feed, administration higher fatty acid/high calorie of breakfast or lower fat/stdn breakfast after 30 minutes the time, according to studying amoxicillin products and the 240mL tap water of accepting oral administration at random.
Typical clinical study position meals will be after dosed administration be provided 4 and 9 hours the time, and after this are being provided at reasonable time.For all experimenters, take identical menu and meals schedule without exception.
Between the research restricted period, the beverage that contains alcohol, caffeine, xanthine and/or grapefruit is restricted.
Adversary and mouth carry out the conformability inspection to guarantee the picked-up of each dosage.
After drug administration, the experimenter will still keep walking about or just sit first 4 hours.Yet, whenever all should there be opposite incident, the experimenter can be inserted suitable position or be lain down in its right side.During restricted, the experimenter can not carry out aggravating activities at any time.
(d) blood sampling scheme
Blood sample (3mL) will be drawn in lavender top/EDTA vacuum test tube in the following time: before dosage behind (0 o'clock) and the dosage 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,8,10,12,14,16 and 24 hour.Intravenous catheter can be used as substituting of perpendicular insertion.
To collect 21 blood samples during each cycle, each experimenter is gathered 63 blood samples altogether.Thus, will gather 189mL blood to the experimenter during studying carries out pharmaceutical analysis and gathers 60mL blood (screening 15mL and stop or during premature termination 15mL in each cycle) being used for the clinical trial evaluation.From female subject, gather other 20mL when 5mL (when 5mL is used in screening be used in each time inspection with) and carry out the serum pregnancy tests.
Before handling and storing, blood sample is stored on ice (can accept fluorescent lighting).Separate plasma sample by centrifugal (about 2500rpm. * 15 minutes, 4 ℃) (in 30 minutes) as early as possible.Blood plasma in each sample should be distributed in the multiple pipe (the minimum 0.5mL of every pipe) with approximately equalised volume.After gathering in about 0 minute, sample is stored to is arranged on or is lower than in the container (polypropylene) of the visible marking in-80 ℃ the refrigerating apparatus, till taking-up is measured.To put the standard barcode label with clinical trial the sample storage vessel will be carried out mark.
When end cycle, sample is analyzed transferring in the bioanalysis laboratory through the express delivery of spending the night on the dry ice.
(e) be used for the bioanalytical method of plasma analysis
Confirm guide according to FDA industry-bioanalytical method, in May calendar year 2001, utilize the verified bioanalytical method of amoxycilline Trihydrate bp that in the scope of 0.05 μ g/mL-25 μ g/mL, is applicable to that plasma sample is analyzed.
(f) method of calculating section AUC
Calculate for part A UC, use trapezoidal the adding and rule of normal linearity in each timed interval.From average pharmacokinetics profile, calculate part A UCs, for example calculate the average amoxycilline Trihydrate bp plasma concentration of single mean P K profile as all experimenters when each time point.For 0~2 hour time, part A UC was AUC (0-2), for 2~5 hours time, part A UC was AUC (2-5)With for time 5-12 hour, part A UC is AUC (5-12), wherein various piece AUC is that the standard pharmaceutical industry pharmacokinetics method of calculation that provide below the basis are calculated:
AUC (0-2), utilize the area under pharmaceutical concentration-time curve in linear 0~2 hour time of trapezoidal addition calculation.
AUC (2-5), utilize the area under pharmaceutical concentration-time curve of linear trapezoidal addition calculation in 2~5 hours.
AUC (5-12), utilize the area under pharmaceutical concentration-time curve in the linear trapezoidal addition calculation 5~12 hours.
Then, by using each AUC (2-5)Value and AUC (5-12)Value is divided by AUC (0-2)Value is come the calculating ratio.
Embodiment 2
Preparation
Preparation contains immediate-release component (pulse 1); First postpones to discharge the amoxycilline Trihydrate bp tablet (applicant's MP) that component (pulse 2) and second postpones to discharge component (pulse 3).After picked-up, this tablet is degraded rapidly.
1. the description of product
Applicant's MP tablet, 775mg is three pulsed dosage forms.This tablet is to discharge pill (pulse 2,30% and pulse 3,25%) by the delay that instant-free particle (pulse 1,45%) and two kinds of functions are applied to mix and prepare.Protective film with non-functional is applied on the tablet then.
The qualitative composition, pharmaceutical grade and the function that comprise the single component of each formulation are listed among the table 1-1.
Table 1-1 applicant's MP tablet, the qualitative composition of 775mg
2. applicant's MP tablet, the quantitative composition of 775mg
Applicant's MP tablet, 775mg, the quantitative composition of amoxycilline Trihydrate bp granula, amoxycilline Trihydrate bp nuclear pill and pulsation pill is arranged in table 2-1~2-5.
2.1 applicant's MP tablet, 775mg
That makes a collection of 144.9kg contains the 891.2mg Utimox, is equivalent to the applicant's of 775mg amoxycilline Trihydrate bp MP tablet, 775mg.Total tablet weight is approximately 1.5 grams.Applicant's MP tablet, the quantitative composition of 775mg is listed in the table below among the 2-1.
Table 2-1 applicant's MP tablet, the quantitative composition of 775mg
*The solid weight percentage
2.2 Utimox (97%) granula
Make Utimox (97%) particle of a collection of 20kg.Amoxicillin granules serves as the pulse 1 of final preparation.Granula is suppressed with pill and other inert component of pulse 2 and 3, thereby form tablet core.
The known standard wet type of those skilled in the art particle method is used to prepare amoxicillin granules.The wet type granula is discharged and is fed in the dome extruding granulator.Then, extruding dry regular time of granula or till the LOD of granula (weight loss on drying) is suitable for described preparation, being generally less than 15% humidity.Then, in the rotating impeller sieve apparatus, the exsiccant granula is sieved.With the material collection of grinding in bucket.Utimox (97%) particulate is quantitatively formed among the 2-2 that is listed in the table below.
Table 2-2 Utimox (97%) particulate is quantitatively formed (being used for pulse 1 in compressible blend)
Component w/w%
The amoxycilline Trihydrate bp, USP 97.0
Polyvinylpyrrolidone, USP (Kollidon 30) 3.0
Amount to 100.0
2.3 Utimox (92%) nuclear pill
Make Utimox (92%) the nuclear pill of a collection of 20kg.To amoxycilline Trihydrate bp nuclear pill coating functions film coating, thereby form pulse 2 and 3 pills.
Utilize the wet type granulation, extrude, the operation of equipment preparation nuclear pill of balling-up, fluidised bed drying and screening.The quantitative composition of Utimox (92%) nuclear pill is listed in the table below among the 2-3.
The quantitative composition (being used for amoxycilline Trihydrate bp pulse 2 and 3 pills) of table 2-3 Utimox (92%) nuclear pill
Component w/w%
The amoxycilline Trihydrate bp, USP 92.0
Microcrystalline Cellulose, NF (Avicel PH101) 5.0
Polyvinylpyrrolidone, USP (PVP K30) 2.0
Polyoxyl 35 Viscotrol C, NF (polyoxyethylenated castor oil) 1.0
Amount to 1000
2.4 Utimox (76.7%) pulse 2 pills
Utimox (76.7%) pulse 2 pills that prepare a collection of 16.8kg by the Eudragit L30D-55 that applies the increase of 20% total solid weight for 14.0kg Utimox (92%) nuclear pill.
Apply previously prepared nuclear pill by function film dressing and prepare pulse 2 pills with the methacrylic acid copolymer dispersion of 20%w/w.Before coating process, prepare the dispersion of Sipacril 2739OF according to shop instruction.Utilization is equipped with the fluidized-bed bottom sprayer of suitable shower nozzle and fixed leg clearance distance, and dispersion is applied on the nuclear pill of amoxycilline Trihydrate bp.
Then, pill is suitably sieved.Pulse 2 pills in amoxycilline Trihydrate bp can be remained under the ambient storage condition, until further handling.The quantitative composition of Utimox (76.7%) pulse 2 pills is listed in the table below among the 2-4.
The quantitative composition of table 2-4 Utimox (76.7%) pulse 2 pills
Component w/w%
The amoxycilline Trihydrate bp, USP 76.7
Microcrystalline Cellulose, NF (Avicel PH101) 4.2
Polyoxyl 35 Viscotrol C, NF (polyoxyethylenated castor oil) 0.8
Polyvinylpyrrolidone, USP (PVP K30) 1.7
Methacrylic acid copolymer dispersion, NF (Eudragit L30D-55) 10.4 *
Talcum, USP (Imperial 1885L) 5.2
Triethyl citrate, NF 1.0
Amount to 100
The solid weight percentage
2.5 Utimox (76.0%) pulse 3 pills
Utimox (73.6%) pulse 3 pills that prepare a collection of 12.5kg by the AQOATAS-HF outer coatings of dressing and the increase of 20% total solid weight at the bottom of the Eudragit L30D-55 that applies the increase of 5% total solid weight to 10.0kg Utimox (92%) nuclear pill.
Before end art for coating, prepare the dispersion of Sipacril 2739OF according to shop instruction.Prepare second coating substance according to shop instruction.Then, utilize and be used to prepare the identical fluidized-bed bottom sprayer of pulse 2 pills, end coatings is applied on the nuclear pill of amoxycilline Trihydrate bp.
Then, immediately the second dressing dispersion is applied to still on the end coated pill in the sprayer of fluidized-bed bottom.The atom gasification that will be used for second art for coating is arranged under the pressure identical with end art for coating.When all dispersions all were applied in, coating processes was finished.After drying cycle, final coating pill is cooled off.The quantitative composition of Utimox (73.6%) pulse 3 pills is listed in the table below among the 2-5.
The quantitative composition of table 2-5 Utimox (73.6%) pulse 3 pills
Component w/w%
The amoxycilline Trihydrate bp, USP 73.6
Microcrystalline Cellulose, NF (Avicel PH101) 4.0
Polyoxyl 35 Viscotrol C, NF (polyoxyethylenated castor oil) 0.8
Polyvinylpyrrolidone, USP (PVP K30) 1.6
Methacrylic acid copolymer dispersion, NF (Eudragit L30D-55) 2.5 *
Acetic acid amber hypromellose, NF (AQOAT AS-HF) 9.6
Talcum, USP (Imperial 1885L) 4.1
Triethyl citrate, NF 3.5
Sodium Lauryl Sulphate BP/USP, NF 0.3
Amount to 100
The solid weight percentage
For example, by with described product once a day to human administration 10 days, the said products can be used for the treatment of human streptococcus pyogenes.
Embodiment 3
The nuclear pill that discharges film coating embodiment 2 parts 2.3 with non-functional immediately applies, thereby forms pulse 1 pill.Place pouch, capsule or can be used for sending simultaneously three kinds of other forms by pill, pulse 1 pill of embodiment 2 and pulse 2 and pulse 3 pills are used with the smalls product form for the pulse of particle form with pulse 1, pulse 2 and pulse 3.In one embodiment, pulse 1, pulse 2 and pulse 3 are mixed, thereby 45%, 30% and 25% pulse 1, pulse 2 and pulse 3 are provided respectively.
Described pulse 1,2 can be become the smalls product with 3 formulated in combination; For example, twice product every day that contains 475mg or 775mg amoxycilline Trihydrate bp.In another embodiment, pulse 1,2 and 3 can be mixed into the product of smalls once a day that contains 775mg or 1250mg or 1550mg amoxycilline Trihydrate bp.Described smalls product can be spread pomace, yoghourt or other is used for the soft diet product of administration.Should not chew or crush product.
Embodiment 4
Utilize the method for embodiment 1 and the lower fat feed state system of embodiment 1 that the amoxicillin products of embodiment 2 is tested.At the described amoxicillin products in this research, determine following part A UC ratio.
Research AUC(2-5)/AUC(0-2) AUC(5-12)/AUC(0-2)
1 2.9∶1 1.3∶1
In addition, utilize the method for embodiment 1 and the lower fat feed state system of embodiment 1 that the amoxicillin products of embodiment 2 is tested, but carry out in the multiple doses mode.Administration every day product once continues seven days, at first day and the 7th day extraction blood and analyze.When the 7th day zero point, there is not obvious accumulation, therefore these multiple doses data can be regarded as two single dose researchs.Thus, in the 1st day and the 7th day determining section AUC ratio of administration amoxicillin products, and in being provided in the following table.
My god AUC(2-5)/AUC(0-2) AUC(5-12)/AUC(0-2)
1 3.6∶1 2.5∶1
7 3.6∶1 2.2∶1
Embodiment 5
Utilize the method for embodiment 1, utilize higher fatty acid feed state system that the amoxicillin products of embodiment 2 is tested.
Gained part A UC ratio is as follows:
AUC (2-5)/AUC (0-2) AUC (5-12)/AUC (0-2)
2.7∶1 1.7∶1
Embodiment 6
Utilize the method for embodiment 1, under fasting, lower fat feed state and higher fatty acid feed state system, the amoxicillin products of embodiment 2 is tested.The AUC of fasting, lower fat feed and higher fatty acid feed test 0-∞Be respectively about 31.5 μ g hours/mL.
Embodiment 7
Method according to embodiment 1 is tested the product of embodiment 2, but the dosage of amoxycilline Trihydrate bp is 1550mg (2x) and is 2325mg (3x) in second system in a kind of system.
Dosage Feed state system AUC (2-5)/AUC (0-2) AUC (5-12)/AUC (0-2)
2x-1550mg Higher fatty acid 2.4∶1 1.6∶1
2x-1550mg Lower fat 5.0∶1 2.5∶1
3x-2325mg Higher fatty acid 2.8∶1 1.6∶1
Embodiment 8
Dissolving method
Utilization is measured the dissolution rate of medicament production at 37 ℃ of USP Apparatus II (oar) that starch fast 75rpm down.This technology is abideed by the method in the USP general rules 711-dissolving usually.Other parameter of carrying out this test method is as described below.The initial dissolve medium that uses is the 0.05M phosphate buffered saline buffer of pH about 2.0.After under about 2.0 pH value, having dissolved 30 minutes, in about 5 minutes clock times, the pH value of medium is adjusted to about 6.0 with 5M KOH solution.After about 6.0, in about 2.5 hours time, make linear about 7.8 the pH value terminal point that is increased to of pH value of medium with 0.5M KOH solution at the pH value stabilization.Reach be used for dissolved pH value terminal point after, made oar operation in addition 30 minutes.When 15 minutes, 30 minutes, 60 minutes, 90 minutes and 210 minutes, sample is drawn.Utilize the UV/VIS spectrophotometer, under the wavelength of 230nm, utilize external standard method that sample is analyzed.
Embodiment 9
Utilize the method for embodiment 8 that the amoxicillin products of embodiment 2 is tested.
The dissolving profile is as follows:
Time (hour) Dissolving %
0.25 37
0.5 39
1 68
1.5 82
2 92
According to above-mentioned instruction, multiple modification of the present invention and variant all are possible; Therefore, unless described in claim, the present invention is not limited to described embodiment.

Claims (29)

1. amoxicillin products comprises: the release component of at least a modification, and the release component of wherein said at least a modification comprises amoxycilline Trihydrate bp and pharmaceutically acceptable carrier at least; When under the state on the feed during with the single dose administration, described product has at least 2.0: 1 AUC (2-5)With AUC (0-2)Ratio and at least 1.1: 1 AUC (5-12)With AUC (0-2)Ratio, when when embodiment 1 measures herein.
2. the product of claim 1, wherein AUC (2-5)With AUC (0-2)Ratio be at least 2.2: 1.
3. the product of claim 1, wherein AUC (2-5)With AUC (0-2)Ratio be at least 2.4: 1.
4. the product of each claim of front, wherein AUC (5-12)With AUC (0-2)Ratio be at least 1.2: 1.
5. the product of each claim of front, wherein AUC (5-12)With AUC (0-2)Ratio be at least 1.3: 1.
6. the product of each claim of front, wherein AUC (2-5)With AUC (0-2)Ratio be no more than 10: 1.
7. the product of each claim of front, wherein AUC (2-5)With AUC (0-2)Ratio be no more than 8: 1.
8. the product of each claim of front, wherein AUC (2-5)With AUC (0-2)Ratio be no more than 6: 1.
9. the product of each claim of front, wherein AUC (5-12)With AUC (0-2)Ratio be no more than 10: 1.
10. the product of each claim of front, wherein AUC (5-12)With AUC (0-2)Ratio be no more than 8: 1.
11. the product of each claim of front, wherein AUC (5-12)With AUC (0-2)Ratio be no more than 6: 1.
12. amoxicillin products, comprise: at least a release component that comprises the modification of amoxycilline Trihydrate bp, described product has the basis average dissolution in vitro profile of the method mensuration of embodiment 8 herein, wherein when following time, the dissolving per-cent of whole amoxycilline Trihydrate bps of described product is no less than for the following minimum dissolving per-cent of described time rule and is not more than following largest percentage into described time rule:
Time (hour) Minimum (%) Maximum (%) 0.25 25 55 0.5 30 60 1 50 85 1.5 70 95 2 85 -
13. the product of each claim of front, it has the basis average dissolution in vitro profile of the method mensuration of embodiment 8 herein, wherein when following time, whole amoxycilline Trihydrate bps dissolving per-cents of described product are no less than for the following minimum dissolving per-cent of described time rule and are not more than following largest percentage into described time rule:
Time (hour) Minimum (%) Maximum (%) 0.25 30 50 0.5 35 55 1 55 80 1.5 75 90 2 90 -
14. the product of each claim of front, it has the basis average dissolution in vitro profile of the method mensuration of embodiment 8 herein, wherein when following time, total amoxycilline Trihydrate bp dissolving per-cent of described product is no less than for the following minimum dissolving per-cent of described time rule and is not more than following largest percentage into described time rule:
Time (hour) Minimum (%) Maximum (%) 0.25 35 45 0.5 35 45 1 65 75 1.5 75 85 2 90 -
15. the product of each claim of front, wherein said product further comprises immediate-release component.
16. the product of each claim of front, the release component of wherein said modification is selected from: postpone to discharge component, slowly-releasing component and above-mentioned combination.
17. the product of each claim of front, the release component of wherein said modification is the slowly-releasing component.
18. the product of claim 1-16, the release component of wherein said modification are to postpone to discharge component.
19. the product of each claim of front, wherein when under state or the fasting state on the feed during with the single dose administration, described product has and accounts for the AUC that discharges amoxicillin products immediately 0-∞At least 75% AUC 0-∞, the wherein said AUC that discharges amoxicillin products immediately 0-∞Be that state or fasting state are measured down on the feed.
20. the product of each claim of front, it comprises comprising the amoxycilline Trihydrate bp and begin to discharge first of amoxycilline Trihydrate bp after immediate-release component and postpones to discharge component and comprise the amoxycilline Trihydrate bp and begin to discharge second of amoxycilline Trihydrate bp after first postpones to discharge component to postpone to discharge component.
21. the product of each claim of front, wherein said product are twice product every day.
22. each product of claim 1-20, wherein said product be comprise the amoxycilline Trihydrate bp every day dosage product once a day.
23. the product of each claim of front, wherein said product contains the amoxycilline Trihydrate bp of the 200mg that has an appointment~about 2500mg.
24. the product of each claim of front, wherein said product contains the amoxycilline Trihydrate bp of the 775mg that has an appointment.
25. the product of each claim of front is when having degree of absorption of equal value during administration on the feed with under the fasting state.
26. the method for a treatment infectation of bacteria in patient or experimenter comprises: to the product of patient or each claim of experimenter's administration front.
27. each product is used for purposes in the medicine of patient or experimenter treatment infectation of bacteria in manufacturing among the claim 1-25.
28. the product of each claim of front, it further comprises Clavulanate or other beta-lactamase inhibitor.
29. the method for a treatment infectation of bacteria in patient or experimenter comprises: to the product of patient or experimenter's administration claim 28.
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